Switching among equivalents in chronic cardiovascular therapies : 'real world' data from Italy

Since August 2012, Italian general practitioners are required to prescribe the generic name of medicines, except for refill of chronic therapy. We evaluated the extent of switching among equivalents in chronic cardiovascular therapies, the influence of the 2012 regulatory intervention and of patient-related or drug-related factors. Prescription of off-patent antiarrhythmics, oral antidiabetics, and ACE-inhibitors dispensed from August 2011 to August 2013 within the Bologna Local Health Authority (870,000 inhabitants) were collected. The rate of actual switching among equivalents was evaluated monthly. The effect of the regulatory intervention was estimated by interrupted time series analysis. Adjusted odds ratios (aORs) of switching were calculated for: age, gender, number of different equivalents available for each drug, change in dispensing pharmacy between subsequent refills. The average monthly rates of switches were 9.6%, 16.3%, and 16.3% for antiarrhythmics, antidiabetics, and ACE-inhibitors, respectively. Values significantly increased soon after the regulatory intervention for ACE-inhibitors (+1.81%, p=0.00), antiarrhythmics (+1.46%, p=0.01) and antidiabetics (+1.09%, p=0.01), and no significant decreasing trends were observed in the following 12 months. For all drug classes, odd of switching was higher in case of change in dispensing pharmacy (up to aOR=4.31, 95CI=4.26-4.35 for ACE-inhibitors) and availability of ≥5 different equivalents (up to aOR=7.82, 95CI=7.39-8.28 for antidiabetics). Switching was lower for age ≥65 for antidiabetics and ACE-inhibitors (aOR=0.92, 95CI=0.90-0.93; 0.87, 0.86-0.88, respectively). The Italian regulatory intervention generated an immediate increase, not sustained in time, in switching among equivalents of cardiovascular therapies. Young age, high number of available equivalents and changes in dispensing pharmacy between subsequent refills were associated with switching

The Contribution of National Spontaneous Reporting Systems to Detect Signals of Torsadogenicity: Issues Emerging from the ARITMO Project

Introduction: Spontaneous reporting systems (SRSs) are pivotal for signal detection, especially for rare events with a high drug-attributable component, such as torsade de pointes (TdP). Use of different national SRSs is rarely attempted because of inherent difficulties, but should be considered on the assumption that rare events are diluted in international databases. Objective: The aim was to describe TdP-related events associated with antipsychotics, H1-antihistamines and anti-infectives in three national SRSs (in Italy, Germany and France) and highlight potential signals of torsadogenicity through a combined literature evaluation. Methods: A common search strategy was applied to extract TdP-related events: (1) TdP, (2) QT interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. Signals of disproportionate reporting (SDRs) were calculated for TdP + QT interval abnormalities and defined by a lower limit of the 95 % confidence interval of the reporting odds ratio (ROR) >1. Among SDRs with at least three cases without concomitant pro-arrhythmic drugs, we defined potential new signal of torsadogenicity as drugs with no published evidence from (a) the crediblemeds® website (http://www.crediblemeds.com, as of November 1st, 2014); (b) studies on the FDA Adverse Event Reporting System (FAERS); and (c) safety trials or pharmaco-epidemiological studies (as of December 16th, 2014). Results: Overall, 3505 cases were retrieved (1372, 1468, and 801 for France, Germany and Italy, respectively). Antipsychotics were mainly recorded in Germany (792 cases), whereas antibiotics peaked at 515 and 491 (France and Italy, respectively). Forty-one drugs met criteria for SDRs in at least one single source, of which 31 were detected only from one single SRS: 18, ten and three (French, German and Italian SRS, respectively). By contrast, only five SDRs were detected in all national data sources (amisulpride, aripiprazole, haloperidol, olanzapine, risperidone). Overall, five potential new signals of torsadogenicity were identified: flupentixol, ganciclovir, levocetirizine, oxatomide and tiapride. Conclusions: We found differences across and within national SRSs in the reporting of drug-induced TdP, which finally resulted in five potential new signals of torsadogenicity. These findings warrant targeted pharmacovigilance studies to formally assess the existence of actual drug–event associations

Antipsychotics and Torsadogenic Risk: Signals Emerging from the US FDA Adverse Event Reporting System Database

Background: Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. Objective: As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Methods: Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org, as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Results: Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82-84.60), cyamemazine (11; 15.48, 6.87-34.91), and olanzapine (189; 7.74, 6.45-9.30). Conclusions: This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

AIM: To inform clinicians on the level of hepatotoxic risk among antimycotics in the post-marketing setting, following the marketing suspension of oral ketoconazole for drug-induced liver injury (DILI). METHODS: The publicly available international FAERS database (2004-2011) was used to extract DILI cases (including acute liver failure events), where antimycotics with systemic use or potential systemic absorption were reported as suspect or interacting agents. The reporting pattern was analyzed by calculating the reporting odds ratio and corresponding 95%CI, a measure of disproportionality, with time-trend analysis where appropriate. RESULTS: From 1687284 reports submitted over the 8-year period, 68115 regarded liver injury. Of these, 2.9% are related to antimycotics (1964 cases, of which 112 of acute liver failure). Eleven systemic antimycotics (including ketoconazole and the newer triazole derivatives voriconazole and posaconazole) and terbinafine (used systemically to treat onychomicosis) generated a significant disproportionality, indicating a post-marketing signal of risk. CONCLUSION: Virtually all antimycotics with systemic action or absorption are commonly reported in clinically significant cases of DILI. Clinicians must be aware of this aspect and monitor patients in case switch is considered, especially in critical poly-treated patients under chronic treatment

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

AIM: To inform clinicians on the level of hepatotoxic risk among antimycotics in the post-marketing setting, following the marketing suspension of oral ketoconazole for drug-induced liver injury (DILI). METHODS: The publicly available international FAERS database (2004-2011) was used to extract DILI cases (including acute liver failure events), where antimycotics with systemic use or potential systemic absorption were reported as suspect or interacting agents. The reporting pattern was analyzed by calculating the reporting odds ratio and corresponding 95%CI, a measure of disproportionality, with time-trend analysis where appropriate. RESULTS: From 1687284 reports submitted over the 8-year period, 68115 regarded liver injury. Of these, 2.9% are related to antimycotics (1964 cases, of which 112 of acute liver failure). Eleven systemic antimycotics (including ketoconazole and the newer triazole derivatives voriconazole and posaconazole) and terbinafine (used systemically to treat onychomicosis) generated a significant disproportionality, indicating a post-marketing signal of risk. CONCLUSION: Virtually all antimycotics with systemic action or absorption are commonly reported in clinically significant cases of DILI. Clinicians must be aware of this aspect and monitor patients in case switch is considered, especially in critical poly-treated patients under chronic treatment

Pro-arrhythmic potential of oral antihistamines (H1) : combining adverse event reports with drug utilization data across Europe

Background. There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in ’90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines. Aim. To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries. Methods. We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance.Results. Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible.Conclusions. Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance

Macrolides and Torsadogenic Risk: Emerging Issues from the FDA Pharmacovigilance Database

Introduction: Concern exists on the pro-arrhythmic potential of macrolides, namely Torsade de Pointes (TdP). Recent evidence has challenged the common opinion of considering azithromycin a safer therapeutic option, causing emerging regulatory and clinical interest. Materials and Methods: We analyzed cases of drug-induced TdP (2004-2011) submitted to the publicly available FDA Adverse Event Reporting System (FAERS). Four groups of mutually exclusive events were identified in decreasing order of drug-attributable risk: 1) TdP; 2) QT interval abnormalities; 3) ventricular arrhythmia (VA); 4) Sudden Cardiac Death (SCD). They were combined into case definition A (TdP/QT abnormalities) and case definition B (VA/SCD). Both case-by-case analysis (information on concomitant drugs, especially QT-prolonging agents listed by Arizona CERT, and disproportionality approach (Reporting Odds Ratio, ROR, with 95%CI) were carried out. Results: Over the 8-year period, macrolides were associated with 183 and 419 cases of interest (case definition A and B, respectively). Clarithromycin was the most frequently reported (84 and 162 cases), followed by azithromycin (63 and 140). Only 27% of cases of TdP/QT abnormalities with azithromycin occurred in patients >65 years of age (63, 47 and 44% for clari-, ery- and telithromycin, respectively). In cases of TdP/QT abnormalities, concomitant QT-prolonging drugs (Arizona CERT lists 1 or 2) were recorded with a proportion very different among macrolides (11 to 89%). The highest percentage of fatal outcome was recorded for azithromycin (17%). Disproportionality was found for azithromycin, clarithromycin and telithromycin for both events of interest, whereas erithromycin showed disproportion only for TdP/QT abnormalities. Conclusions: Despite inherent limitations of spontaneous reporting analyses, the remarkable proportion of fatal cases and the occurrence of TdP-related events in middle-aged patients strengthen the view that caution is needed before considering azithromycin as a safer therapeutic option among macrolides

Dipeptidyl peptidase-4 inhibitors and heart failure: Analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System

Background and aims: We tested the possible association between dipeptidyl peptidase-4 inhibitors (DPP-4-I) use and heart failure (HF) occurrence by assessing the publicly available US-FDA Adverse Event Reporting System (FAERS). Methods: FAERS data reporting HF and DPP-4-Is use in the period from the fourth quarter of 2006 through 2013 were extracted, using the Standardized MedDRA Query "Cardiac failure". Disproportionality (case/non-case method) was implemented by calculating Reporting Odds Ratios (RORs) with 95% Confidence Interval (CI): (1) exploratory analysis on the entire FAERS (using rosiglitazone as positive control); (2) consolidated analyses by therapeutic area (within antidiabetics), correcting for event- and drug-related competition bias and adjusting for co-reported drugs as confounders. Results: HF during DPP4-I use was recorded in 390 reports (4.4% of total reports). In exploratory analysis, statistically significant ROR emerged for DPP-4-I as a class (ROR = 1.17; 95% CI = 1.05-1.29), saxagliptin (1.68; 1.29-2.17), vildagliptin (2.39; 1.38-4.14), and rosiglitazone (13.98; 13.30-14.70). In consolidated analyses, the ROR for saxagliptin (2.60; 1.92-3.50) and vildagliptin (4.07; 2.28-7.27) increased, and became also significant for sitagliptin (1.61; 1.40-1.86). Concomitant drugs were reported in more than 50% of cases; the adjusted RORs of saxagliptin (2.30; 1.70-3.10), vildagliptin (3.15; 1.76-5.63), and sitagliptin (1.48; 1.28-1.71) were nonetheless significant. Conclusion: FAERS data are consistent with clinical studies on a possible association between saxagliptin and HF. The disproportionate reporting of HF with sitagliptin, conflicting with a recent phase IV trial, suggests that cardiovascular safety requires close post-marketing vigilance by clinicians of individual DPP-4-I in the community until the issue of class effect is solved

Use of phytoestrogens and effects perceived by postmenopausal women: result of a questionnaire-based survey

BACKGROUND: Use of food supplements-containing phytoestrogens among postmenopausal women is rapidly increasing. Although phytoestrogens are often perceived as safe, evidence for overall positive risk-benefit profile is still inconclusive. The chance to buy them by user's initiative does not facilitate surveys on their prevalence and pattern of use. The aim of this study was to describe the pattern of use and self-reported positive and negative perceptions of phytoestrogens in post-menopausa. METHODS: A questionnaire was administered to women who were buying food supplements containing phytoestrogens in 22 pharmacies located in the Bologna area (400,000 inhabitants). Questionnaire was structured into 3 sections: (a) socio-demographic information, (b) pattern of use, (c) positive and negative perceptions. RESULTS: Data on 190 peri- and post-menopausal women (aged 38-77) were collected. Women stated to use phytoestrogens to reduce hot flushes (79%), insomnia (15%), mood disturbances (14%) and prevent osteoporosis (15%). The majority (59%) took phytoestrogens routinely, whereas 28% in 3-month cycles. Among positive perceptions between short- and long-term users, a not negligible difference was reported for relief of hot-flushes (68% in short-term vs. 81% in long-term users; p = 0.04). Negative perceptions were reported more frequently in the long-term group, and this difference was statistically significant for edema (6% in short-term vs. 17% in long-term users; p = 0.04), but not for other effects: e.g., swelling sensation (10% vs. 21%; p = 0.09), somnolence (7% vs. 10% p = 0.62), fatigue (4% vs.11% p = 0.15). CONCLUSIONS: In the Bologna area, the pattern of use of phytoestrogens for menopausal symptoms is heterogeneous, and women overall find these substances to be beneficial, especially for relief of hot-flushes. Other positive perceptions decreased with long-term use. Negative perceptions, especially estrogen-like effects, seem to be infrequent and increase with long-term therapy. Physicians should pay attention to effects perceived by post-menopausal women and routinely monitor the use of phytoestrogens, in order to recognize possible adverse effects and actual benefits

Social and clinical descriptors of antipsychotic prescription

OBJECTIVE: To identify descriptors of Antipsychotic (AP) prescription, focusing on second generation antipsychotics (SGAs), polypharmacy, and long-acting injections (LAIs). METHODS: Outpatients of the Bologna-Community-Mental-Health-Centres with at least one AP prescription were selected. Patients' characteristics, service utilization, and AP prescriptions were collected from administrative databases. Prescriptions were grouped by class (SGA vs. First Generation Antipsychotics), drug combination (polypharmacy vs. monotherapy), and preparation (LAIs vs. regular administration). Multi-variate analyses were performed to identify prescription descriptors among socio-demographic and clinical variables. RESULTS: Among 6,074 patients and 41,121 AP prescriptions, SGAs were used in 70.7% of subjects, AP polypharmacy in 25.3%, and LAIs in 17.5%. SGAs were prescribed more often for young, Italian patients, with higher education, voluntary hospitalization, and high number of visits. Descriptors of AP polypharmacy were: high number of visits and hospitalization, length of treatment, non-urban residency, male gender, unemployment. Characteristics associated to LAI prescription were: long duration of treatment, high number of visits, compulsory admissions, non-Italian nationality, male gender, age\u2009>\u200934, low education, unmarried status. CONCLUSIONS: Besides illness severity, this study identified different socio-demographic descriptors of AP choices, raising concerns on the equity of treatments. Efforts should be directed to investigate appropriateness of AP treatments especially in social disadvantaged populations